The aim of this project is to study the human T lymphotropic virus type I (HTLV-I) origin and evolution, and its pathogenetic role in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To study the origin, evolution and HTLV-I dissemination in the world, we analyzed viral sequence from ex vivo samples of infected individuals, whose origin, clinical diagnosis and general background was known. Using this approach, we were able to identify a novel HTLV-I variant in the southwestern Pacific Islands and formally prove that HTLV-I was disseminated in the New World through slave trade events. We plan to extend our genetic studies to the close HTLV-I relatives (simian T cell leukemia virus) which are found in naturally infected monkeys. We are investigating the pathogenetic role of HTLV-I in HAM/TSP from three different angles: 1) by studying which viral genes are expressed in the cells of infected patients. For example, in this study we identify novel HTLV-I spliced mRNAs; 2) by developing an animal model (rabbits first and perhaps monkeys later) for HAM/TSP using field viral isolates from patients rather than culture adapted HTLV-I; and 3) testing the effect of special antiviral therapy (antisense oligonucleotides or retroviral vector carrying molecular decoys) in vitro and in vivo (in rabbits) targeting specific HTLV-I genes.